Germline testing recommendation (GTR) in non-small cell lung cancer (NSCLC) after broad tumor sequencing: evaluating the impact of more/less conservative criteria from ESMO/ASCO

Keywords

Germline testing - Non-Small Cell Lung Cancer (NSCLC) - Next-generation Sequencing (NGS)

Introduction: Access to next-generation sequencing (NGS) has increased the detection of actionable variants in cancer drivers. However, distinguishing between germline and somatic mutations remains a significant challenge in tumor-only NGS. Given the potential implications for patient care and familial risk, identifying potential germline variants in non-squamous NSCLC has become increasingly important.

Objective: To determine the proportion of NSCLC cases that meet different criteria for germline testing based on conservative thresholds from ESMO and ASCO guidelines.

Methods: Retrospective analysis using anonymized NGS data (180, 395 or 700+ gene panels) from patients eligible to Lung Map Consortium at Oncoclinicas Medicina de Precisão (OCPM) and Boston Lighthouse Innovation (BLI) labs from April 2021 to August 2024. Variants were filtered using three gene lists: ESMO More Conservative (9 genes), ESMO Less Conservative (21 genes) and ASCO Less Conservative (34 genes). GTR were calculated for each category, considering only pathogenic/likely pathogenic variants with a variant allele frequency (VAF) ≥ 20%.

Results: NGS data from 1,468 cases were evaluated. Median age was 70 years (21-97), with most samples from the Southeast (64.5%) and Northeast (16.5%) regions. GTR for the ESMO More Conservative, ESMO Less Conservative and ASCO Less Conservative were 1.4% (n = 20), 3.9% (n = 58) and 11.9% (n = 175), respectively. The most frequently mutated genes in ESMO More Conservative list were BRCA2 (n = 5), EGFR T790M (n = 4), RET (n = 4), and TP53 R337H (n = 3). In the ESMO Less Conservative list, BRIP1 (n = 14), MUTYH (n = 11), TSC2 (n = 5), PMS2 (n = 4), RAD51C (n = 3) were predominant. Finally, in the ASCO Less Conservative criteria the most frequent genes were ATM (n = 71), NF1 (n = 35) and PTCH1 (n = 12).

Conclusion: Our findings indicate that using more conservative ESMO criteria, less than 4% of advanced NSCLC would qualify for germline testing after tumor-only NGS. However, up to 12% would be eligible for genetic counseling and germline testing under the less conservative ASCO criteria, primarily due to ATM variants (4.8% of cases). Identifying a larger proportion of NSCLC patients at risk of hereditary cancer syndromes could enhance personalized treatment strategies and familial risk assessments, although broader implementation of these criteria needs further validation.

Corresponding author: Breno Jeha Araújo (e-mail: [e-mail]).